A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity
Abstract Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobac...
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Nature Portfolio
2017
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oai:doaj.org-article:a22e2ae045844aef9db204f3b1fa9c742021-12-02T16:06:57ZA novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity10.1038/s41598-017-04108-72045-2322https://doaj.org/article/a22e2ae045844aef9db204f3b1fa9c742017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04108-7https://doaj.org/toc/2045-2322Abstract Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lead compound. IMB-YH-8 inhibited PknB auto-phosphorylation and the phosphorylation of GarA by PknB in a dose-dependent manner. The compound did not inhibit human Akt1 or other serine/threonine kinases in M. tuberculosis except for the highly homologous PknA. IMB-YH-8 bound to PknB with a moderate affinity. Molecular docking revealed that IMB-YH-8 interacts with the catalytic domain of PknB. Observations of electron microscopy showed that IMB-YH-8 changed the morphology of H37Rv and disrupted the cell wall. The differential transcriptional response of M. tuberculosis to IMB-YH-8 revealed changes in SigH regulatory pathways modulated by PknB. Notably IMB-YH-8 not only potently inhibited drug-sensitive and multidrug-resistant clinical isolates but also exhibited a dose dependent inhibition of intracellular M. tuberculosis. Taken together, these in vitro data demonstrate that IMB-YH-8 is a novel inhibitor of PknB, which potently prevents growth of M. tuberculosis. It is as yet unclear whether inhibition of PknA contributes to the anti-tubercular action of IMB-YH-8.Jian XuJu-xian WangJin-ming ZhouChang-liang XuBin HuangYun XingBin WangRui LuoYu-cheng WangXue-fu YouYu LuLi-yan YuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017) |
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Medicine R Science Q Jian Xu Ju-xian Wang Jin-ming Zhou Chang-liang Xu Bin Huang Yun Xing Bin Wang Rui Luo Yu-cheng Wang Xue-fu You Yu Lu Li-yan Yu A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
| description |
Abstract Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lead compound. IMB-YH-8 inhibited PknB auto-phosphorylation and the phosphorylation of GarA by PknB in a dose-dependent manner. The compound did not inhibit human Akt1 or other serine/threonine kinases in M. tuberculosis except for the highly homologous PknA. IMB-YH-8 bound to PknB with a moderate affinity. Molecular docking revealed that IMB-YH-8 interacts with the catalytic domain of PknB. Observations of electron microscopy showed that IMB-YH-8 changed the morphology of H37Rv and disrupted the cell wall. The differential transcriptional response of M. tuberculosis to IMB-YH-8 revealed changes in SigH regulatory pathways modulated by PknB. Notably IMB-YH-8 not only potently inhibited drug-sensitive and multidrug-resistant clinical isolates but also exhibited a dose dependent inhibition of intracellular M. tuberculosis. Taken together, these in vitro data demonstrate that IMB-YH-8 is a novel inhibitor of PknB, which potently prevents growth of M. tuberculosis. It is as yet unclear whether inhibition of PknA contributes to the anti-tubercular action of IMB-YH-8. |
| format |
article |
| author |
Jian Xu Ju-xian Wang Jin-ming Zhou Chang-liang Xu Bin Huang Yun Xing Bin Wang Rui Luo Yu-cheng Wang Xue-fu You Yu Lu Li-yan Yu |
| author_facet |
Jian Xu Ju-xian Wang Jin-ming Zhou Chang-liang Xu Bin Huang Yun Xing Bin Wang Rui Luo Yu-cheng Wang Xue-fu You Yu Lu Li-yan Yu |
| author_sort |
Jian Xu |
| title |
A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
| title_short |
A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
| title_full |
A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
| title_fullStr |
A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
| title_full_unstemmed |
A novel protein kinase inhibitor IMB-YH-8 with anti-tuberculosis activity |
| title_sort |
novel protein kinase inhibitor imb-yh-8 with anti-tuberculosis activity |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/a22e2ae045844aef9db204f3b1fa9c74 |
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